ZA200609429B - Lewis acid mediated synthesis of cyclic esters - Google Patents
Lewis acid mediated synthesis of cyclic esters Download PDFInfo
- Publication number
- ZA200609429B ZA200609429B ZA200609429A ZA200609429A ZA200609429B ZA 200609429 B ZA200609429 B ZA 200609429B ZA 200609429 A ZA200609429 A ZA 200609429A ZA 200609429 A ZA200609429 A ZA 200609429A ZA 200609429 B ZA200609429 B ZA 200609429B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- alkoxy
- hydrogen
- halogen
- hydroxy
- Prior art date
Links
- 230000015572 biosynthetic process Effects 0.000 title claims description 5
- 238000003786 synthesis reaction Methods 0.000 title claims description 5
- 125000004122 cyclic group Chemical group 0.000 title description 2
- 239000002841 Lewis acid Substances 0.000 title 1
- 150000007517 lewis acids Chemical class 0.000 title 1
- 230000001404 mediated effect Effects 0.000 title 1
- -1 cyanomethyl Chemical group 0.000 claims description 139
- 150000001875 compounds Chemical class 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 150000002367 halogens Chemical class 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- CPEONABTMRSIKA-UHFFFAOYSA-N 1,4$l^{2}-oxazinane Chemical compound C1COCC[N]1 CPEONABTMRSIKA-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000001212 derivatisation Methods 0.000 claims description 9
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002950 monocyclic group Chemical class 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 claims 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims 2
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims 1
- 235000010582 Pisum sativum Nutrition 0.000 claims 1
- 240000004713 Pisum sativum Species 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 235000013350 formula milk Nutrition 0.000 description 54
- 150000002431 hydrogen Chemical group 0.000 description 39
- 150000003254 radicals Chemical class 0.000 description 15
- 229920001577 copolymer Chemical class 0.000 description 12
- 239000002253 acid Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
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Description
TRICYCLIC IMIDAZOLPYRIDINES AND INTERMEDIATES FOR THE SYNTHESIS THEROF
The invention relates 10 a process for the preparation of tricyclic imidazopyridines, to valuable inter- mediates used in said process, to new tricyclic imidazopyridines produced with that process and their use in the pharmaceutical industry as active compounds for preparing medicaments.
Prior Art
U.S. Patent 4,468,400 describes tricyclic imidazo[1,2-a]pyridines having different ring systems fused to the imidazopyridine skeleton, which compounds are said to be suitable for treating peptide ulcer disorders. The Intemational Patent Applications W098/42707, WO98/54188, WO00/17200,
WO000/26217, WO 00/63211, WO 01/72756, WO 01/72754, WO 01/72765, WO 01/72757, WO 02/34749, WO 03/014120, WO 03/016310, WO 03/014123, WO 03/068774 and WO 03/091253 dis- close tricyclic imidazopyridine derivatives having a very specific substitution pattern, which compounds are likewise said to be suitable for treating gastrointestinal disorders.
It has now been found that the compounds disclosed for example in WO 03/014123 with X = NH, which were not described by way of example in said patent application, can be prepared with a broad variety of substituents by way of a general reaction sequence starting from novel intermediates. pp.
The invention thus relates in a first aspect to compounds of the formula 1,
R3 =~” “N \
R1 xn =N
N Mo
Arom where
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloaliyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1- 4C-alkoxycarbonyl, 2-4C-alkenyl, fluoro-1-4C-alkyl or hydroxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hy- droxy-1-4C-akyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or cyanomethyl,
R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkvl, 1- 4C-alkoxycarbonyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical -CO-NR31R32, where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-atkyl, 8-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical
Arom is a R4-, R6-, R6- and R7-substituted mono- or bicyclic aromatic radical selected from the group consisting of phenyl, naphthyl, pyrolyl, pyrazoiyl, imidazolyl, 1,2.3-triazolyl, indolyl, benzimida- zolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzathiophenyl (ben- zothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinotinyl and isoquinolinyl, where
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-afkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryt-1- 4C-atkoxy, trifluoromethyl, nitro, amino, mono- or di-1 -4C-alkylamino or sulfonyl,
RS is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- draxyl,
R6 is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substituted phenyt having one, two or three identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, halogen, trifluoromethyl, nitro, triffluoromethoxy, hydroxyl and cyano, and their salts. ~g, po 1-4C-Alkyl denotes straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and me- thyl radicals. 3-7C-Cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, among which cyclopropyl, cyclobutyl and cyclopentyl are preferred. 3-7C-Cydloalkyl-1-4C-alkyl denotes one of the abovementioned 1-4C-alky! radicals which is substi- tuted by one of the abovementioned 3-7C-cycloalky! radicals. Examples which may be mentioned are ’ the cyclopropylmethyl, the cyclohexyimethyl and the cyclohexylethyl radicals. 1-4C-Alkoxy denotes radicals which, in addition to the oxygen atom, contain a straight-chain or bran- ched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butaxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy rad!- cals.
1-4C-Alkoxy-1-4C-akyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the meth- oxymethyl, the methoxyethyl and the butoxyethyi radicals. 1-4C-Alkaxycarbonyl (-CO-1-4C-alkoxy) denotes a carbonyl group to which is attached one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl {CH;0-C(O)) and the ethoxycarbonyl (CH3CH,0-C(O)) radicals. 2-4C-Alkenyl denotes straight-chain or branched alkenyl radicals having 2 to 4 carbon atoms. Exam- ples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl (allyl) radi- cals. 2-4C-Alkynyl denotes straight-chain or branched alkynyl radicals having 2 to 4 carbon atoms. Exam- ples which may be mentioned are the 2-butynyl, the 3-butynyl, the 2-propynyl (propargyi) and, pref- erably, the 1-ethynyl, 1-propynyt and 1-butynyl radicals.
Fluoro-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one or more fluorine atoms. An example which may be mentioned Is the trifluoromethyl radical.
Hydroxy-1-4C-alkyl denotes abovementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3- hydroxypropyl radicals. od
For the purpose of the invention, halogen is bromine, chlorine and fluorine. 1-4C-Alkoxy-1-4C-alkoxy denotes one of the abovementioned 1-4C-alkoxy radicals which is substi- tuted by a further 1-4C-alkoxy radical. Examples which may be mentioned are the radicals 2-(methoxy)ethoxy (CH3-O-CH2-CH,-0-) and 2~(ethoxy)ethoxy (CHs-CHz-O-CH,-CH, -O-). 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkoxy-1-4C-alkyl radi- cals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. An example which may be mentioned is the radical 2-(methoxy)ethoxymethyl (CH3-O-CH-CHz-O-CHx).
Fiuoro-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alky! radicals which is substi- tuted by a fluoro-1-4C-alkoxy radical. Here, fiuoro-1-4C-alkoxy denotes one of the abovementioned 1- 4C-alkoxy radicals which is fully or predominantly substituted by fluorine. Examples of fully or pre- dominantly fluorine-substifuted 1-4C-alkoxy which may be mentioned are the 1,1,1 ,3,3,3-hexafluoro-2- propoxy, the 2-yrifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 22,3,3,4,4,4-heptafluoro-1-butoxy, the 4 4 4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfiuoroethoxy, the 1 2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2 2-triflucroethoxy, the triflucromethoxy and preferably the difiuoromethoxy radicals. 1-7C-Alky! denotes straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl-(5-methylthexyl), hexyl, isohexyl-(4-methylpentyl), neohexyl-(3,3-dimethylbutyl), pentyl, isopentyl-(3-methylbutyl), neopentyl-(2,2-dimethyipropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
Carboxy-1-4C-alkyl denotes, for example, the carboxymethyl (-CH ,COOH) or the carboxyethyl {(-CH,CH,COOH) radical.
Di-1-4C-alkylamino denotes an amino radical which is substituted by two identical or different of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the dimethytamino, the diethylamino and the diisopropylamino radicals. 2-4C-Alkenyloxy denotes a radical which, in addition to the oxygen atom, contains a 2-4C-alkenyi ra- dical. An example which may be mentioned is the allyloxy radical.
Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example which may be mentioned is the benzyl radical.
Aryl-1-4C-alkoxy denctes an aryl-substituted 1-4C-atkoxy radical. An example which may be men- tioned is the benzyloxy radical. =.
Mono- or di-1-4C-alkylamino radicals contain, in addition to the nitrogen atom, one or two of the abo- vementioned 1-4C-glky! radicals. Preference is given to di-1 -4C-alkylamino and in particular to di- methyl-, diethyl- or diisopropylamino.
Radicals Arom which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl, 4-acetamidophenyt, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyt, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,6-bis- (triflucromethyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6- flucrophenyl, 3.chloro-4-fluocrophenyl, 2-chioro-5-nitrophenyl, 4-chioro-3-nitrophenyl, 3-(4-chioro- phenoxy)phenyl, 2 4-dichlorophenyl, 3,4-difluorophenyl, 2.4-dihydraxyphenyi, 2,6-dimathoxyphenyi, 3,4-dimethoxy-5-hydroxyphenyl, 2,5-dimethylphenyl, 3-ethoxy-4-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, 3-methoxy-2-nitrophenyl, 3-nitropheny, 2,3,5-trichiorophenyl, 2.4 .6-trihydroxyphenyl, 2,3,4-timethaxyphenyl, 2-hydroxy-1 -naphthyl, 2- methoxy-1-naphthyl, 4-methoxy-1 -naphthyl, 1-methyl-2-pyrrolyl, 2-pymolyl, 3,4-dimethyl-2-pyrvolyl, 5- ethoxycarbonyl-2,4-dimethyl-3-pyrrolyl, 3,4-dibromo-5-methyl-2-pyrroiyt, 2,5-dimethyl-1-phenyl-3- pyrrolyl, 5-carboxy-3-ethyl-4-methyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 2,5-dimethyl-1-(4-
trifiuoromethyliphenyl)-3-pymoiyl, 1{2,6-dichloro-4-trifluoromethylphenyl)-2-pymoll, 1-(2-nitrobenzyl)-2- pyrrolyl, 1-2-fluoraphenyl)-2-pyrolyl, 1-{4-tifluoromethoxyphenyl)-2-pyrolyh 1-(4-ethoxycarbonyl)- 2,5-dimethyl-3-pyrolyl, S5-chloro-1 ,3-dimethyl-4-pyrazolyl, 5-chioro-1-methyl-3-trifiuoromethyl-4- pyrazolyl, 1-(4-chlorobenzyl)-5-pyrazoiyl, 1,3-dimethyi-5~(4-chlorophenoxy)-4-pyrazoiyh, 1-methyl-3- trifiuoromethyl-5-(3-triflucromethylphenoxy)-4-pyrazolyl, 5-allyloxy-1-methyl-3-trifiuoromethyl-4- pyrazolyl, 5-chloro-1 -phenyt-3-triflucromethyl-4-pyrazoiyl, 3 6-dimethyl-1-phenyl-4-imidazolyl, 4-bromo- 1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyt-1,2,3-trdazol-4-yl, 3-indolyl, 4-Indolyl, 7-indoiyl, 5- methoxy-3-indotyl, 5-benzyloxy-3-indotyl, 1-benzyl-3-indolyi, 2-(4-chlorophenyl)-3-indolyl, 7-benzyloxy- 3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyi, 4,5,6,7-tetrafluoro-3-indolyl, 13,5- difluorobenzyl)-3-indolyl, 1-methyi-2-(4-trifluorophenoxy)-3-indolyl, 1-methyl-2-benzimidazolyl, 5-nitro- 2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 4- ethoxycarbonyl-5-methyl-2-furyl, 5~(2-triflucromethoxyphenyl)-2-furyl, 5-(4-methoxy-2-nitrophenyl)-2- furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuryl, 2-thianyl, 3-thienyl, 3-methyl-2-thienyl, A-bromo-2-thienyl, 5-bromo-2-thienyl, S-nitro-2-thienyl, 5-methyl-2- thienyl, 5-{4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-thienyl, §-carbaxy-2-thienyl, 2,5-dichtoro-3-thienyl, 2-benzothienyl, 3-methyl-2-benzothienyl, 2-bramo-5-chloro-3-benzothienyl, 2- thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2 4-dichloro-5-thiazoyl, 2-diethytamino-5-thiazolyl, 3-methyi-4- nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-5-hydroxymethyl-2- methyl-4-pyridyl, 2,6-dichioro-4-pyridyl, 3-chloro-5-trifluoromethyl-2-pyridyl, 4-(4-chlorophenyl)-3- pyridyl, 2-chloro-5-methoxycarbonyl-6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6(3- triflucromethylphenoxy)-3-pyridyl, 2-{4-chlorophenoxy)-3-pyridyl, 2,4-dimethoxy-5-pyrimidine, 2- quinctinyl, 3-quinolinyl, 4-quinolinyl, 2-chloro-3-quinolinyl, 2-chloro-6-methoxy-3-quinolinyl, 8-hydroxy- .. 2-quinolinyl and 4-isoquinolinyl. i.
One aspect (aspect a) of the invention relates to compounds of the formula 1, in which
R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1- 4C-alkoxycarbonyl, fluoro-1-4C-alkoxy-1 -4C-alkyl or the radical -CO-NR31R32, where
R31 Is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and . R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical and R1, R2 and Arom have the meanings as indicated in the outset.
Another aspect (aspect b) of the invention relates to compounds of the formula 1, in which
R3 is the radical -CO-NR31R32,
R31 Is 3-7C-cydoalkyl and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyi, and R1, R2 and Arom have the meanings as indicated in the outset.
The invention further relates to compounds of the formula 1, in which
Ri is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-atkyl, 1- 4C-alkoxycarbonyl, 2-4C-alkenyl, fluoro-1-4C-alkyl or hydroxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloatkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hy- droxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1 -AC-alkyl or cyanomethyl,
R3 is halogen, hydroxy-1-4C-alkyl, 1 -4C-alkoxy-1-4C-alkyl, 1 -4G-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1- 4C-alkoxycarbonyl, fluoro-1-4C-alkoxy-1 -4C-alky! or the radical -CO-NR31 R32, where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-akkoxy-1-4C-alkyl, or where
R31 and R32 together and Including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical
Arom is a Ré4-, R5-, R6- and R7-substituted mono- or bicyclic aromatic radical selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indotyl, benzimida- zolyl, furanyl (fury), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyl (ben- zothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinofinyl, where
R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-alkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1- 4C-alkoxy, triflucromethyi, nitro, amino, mono- or di-1-4C-alkylamino or sulfonyl,
RS is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl orhy- droxyl,
RS is hydrogen, 1-4C-alkyl or halogen and
R7 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substituted phenyl having one, two or three identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, halogen, trifluoromethyi, nitro, trifluoromethoxy, hydroxyl and cyano, . and their salts.
Compounds which are to be mentioned are those compounds of the formula 1, where
R1 is 1-4C-akkyl or 3-7C-cycloatkyl
R2 is hydrogen, 1-4C-alkyl, halogen or fluoro-1-4C-alkyl
R3 Is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1 -AC-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1- 4G-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical
Arom is a R4-, R5-, R6- and R7-substituted phenyl, where
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen or 1-4C-alkl,
R6 is hydrogen or 1-4C-alkyl and
RY7 is hydrogen, and their salts.
Compounds which are also to be mentioned are those compounds of the formula 1, where
R1 Is 1-4C-alkyl or 3-7C-cycloalky!
R2 is hydrogen, 1-4C-alkyl, halogen or fluoro-1-4C-alkyl
R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1 -AC-alkoxy-~1-4C-alkyi, 1- 4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-7C-alkyi, hydroxy-1-4C-alkyl or 1-4C-alkaxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- Ll rolidino, piperidino or morpholino radical
Arom is a R4-, R5-, R8- and R7-substituted phenyl, where
R4 is hydrogen or 1-4C-alkyi,
RS is hydrogen or 1-4C-alkyl,
R6 is hydrogen or 1-4C-alkyl and
R7 Is hydrogen, and their salts.
Compounds which are to be particularly mentioned are those of the formula 1, where
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is halogen, hydroxy-1-4C-alkyt, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-7C-alkyl, hydraxy-1-4C-alkyl, 3-7C~cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkaxy-1-4C-alkyl,
or where
R31 and R32 together and induding the nitrogen atom to which they are attached form a pyr- rofidino, piperidino or morpholino radical
Arom is phenyl, and their salts.
Compounds which are also to be particutarly mentioned are those of the formula 1, where
R1 is 1-4C-akkyl,
R2 is 14C-akyl,
R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl of 1-4G-alkaxy-1-4C-alkyt and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyt or 1-4C-akoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical
Arom is phenyl, and their salts.
Compounds which are also to be particularly mentioned are those of the formula 1, where
R1 is 1-4C-alkyl, .
R2 is 1-4C-akyl,
R3 is halogen, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom fo which they are attached form a pyr- rolidino, piperidino or morphalino radical
Arom is phenyl, and their salts.
Compounds which are also to be particularly mentioned are those of the formula 1, where
R1 is 1-4C-alkyl,
R2 is 14C-akyl,
R3 is halogen, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1 -AC-atkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyi of 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical
Arom Is phenyl, and their salts.
Compounds which are to be emphasized are those of the formula 1, where
R1 is 1-4C-alkyl,
R2 Is 1-4C-alkyl,
R3 is halogen, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-4G-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl or 1-4G-alkaxy-1-4C-afkyl and
R32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalky! or 1-4C-alkaxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino radical
Arom is phenyl, and their salts.
Compounds which are also to be emphasized are those of the formula 1, - .. where
R1 is 1-4C-alkyl,
R2 Is 1-4C-alkyl,
R3 is halogen, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where
R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-atkyl or 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino radical
Arom is phenyl, and their sats.
Compounds which are also to be emphasized are those of the formula 1, where
R1 Is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3 is halogen or 1-4C-alkoxycarbonyl,
Arom is phenyl, and their salts
The invention further relates to the use of compounds of the formula 1, in which R1, R2, R3 and Arom have the meaning as indicated in the outset, for the preparation of compounds of the formula 2 and their salts
R3 =z ~
R1 nN "@
Arom in which R1, R2, R3 and Arom have the meaning as indicated in the outset, which compounds are said to be suitable for treating gastrointestinal disorders.
The following exemplary compounds of the formula 2 (Table 1) can be synthesized from compounds of the formula 1 according to the general procedures outlined in more detail below. Further com- pounds of the formula 2 which are not listed in table 1 can likewise be prepared from the correspond- ing compounds of the formula 1.
Table 1: oo |soorOy |P] (GF [Gf | GRGROGOY [CF | CFs | CNC
GF [GF | HOCRICRAFICOr
CHINCOR
[Ch GH, [FCO i Ee Ca a Lc a Ee Li a ac 23
The invention thus further relates to the compounds of the formula 2 listed in the table 1 above and their salts.
Suitable salts of compounds of the formula 1 and of the formula 2 are — depending on the substitution — in particular all acid addition salts. Particular mention may be made of the pharmacologically accept-
able salts of the inorganic and organic aclds customarily used in pharmacy. Those suitable are water- soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hy- drobromic acid, phosphoric acid, nitric acid, sulfuric adid, acetic acld, citric acid, D-gluconic acid, ben- zoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sutfosalicyfic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesul- fonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in the salt preparation in an equimolar ratio or in a ratio differing therefrom, depending on whether the acid is a mono- or polybasic acid and on which salt ls desired.
Pharmacologically unacceptable salts, which can be Initially obtained, for example, as process prod- ucts in the preparation of the compounds of the formula 1 or of the formula 2 according to the inven- tion on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. it is known to the person skilled in the art that the compounds of the formula 1 or of the formula 2 ac- cording to the invention and their salts can, for example when they are isolated in crystalline form, comprise varying amounts of solvents. The invention therefore also embraces all solvates and, in par- ticular, afl hydrates of the compounds of the formula 1 or of the formula 2, and all solvates and, in par- ticular, all hydrates of the salts of the compounds of the formula 1 or of the formula 2.
The preparation of the compounds of the formula 2 is performed, as shown for example in scheme 1, such that the compounds of the formula 1, in which R1, R2, R3 and Arom have the meanings as indi- cated in the outset, are subjected to a cyclization reaction, for example under acidic conditions, using ~ for example sulphuric acid.
Scheme 1
R2
R3 If desired also
Zz A J Zz {, Er further derivatizations
A — a toother compounds of
N AN N the formula 2 x WM) NH (2)
Arom Arom
Compounds of the formula 2 obtained according to Scheme 1 can be subjected, if desired, to further derivatizations. If compounds of the formula 2 with, for example, R3 = Br are obtained, further chemi- cal transformations, which are known per se, can be performed to synthesize a great variety of other compounds of the formula 2 by reactions known to the expert. If, for example, compounds where R3 = -CO-1-4C-alkoxy or R3 = -CO-NR31R32 are desired, an appropriate derivatization can be performed in a manner knawn per se (e. g. metal catalysed carbonylation of the corresponding bromo compound or conversion of an ester into an amide).
The compounds of the formula 1 according to the invention, in which R1, R2, R3 and Arom have the meanings as indicated in the outset, can be prepared, for example, following the reaction sequence as outlined in Scheme 2 under standard reaction conditions, as described for example in more detail in the examples.
Scheme 2 2 x
R3 Arom H R = ZN
A —_— N—ri
Ny ON NN
NH (3) 4 @)
Arom )
ZZ ugar RZ N Raormangement NE —— N R{ —m—m————— BD R1
NN XN
Lo ® x Mow
Arom Arom
Compounds of the formula 3 with R3= 1-4C-alkoxycarbonyl or -CONR31R32 are known for example from WO 02/20523 or WO 99/55706 or can be prepared with the same or other substituents R3 (for example R3 = halogen) in a manner known to the expert, for example in analogy to the synthesis dis- closed in J. Med. Chem. 1985, 28, 876-892. .-
Compounds of the formula 1 obtained according to Scheme 2 can be subjected, if desired, to further derivatization reactions. If compounds of the formula 1 with, for example, R3 = 1-4C-alkoxycarboryl are obtained, further chemical transformations, which are known per se, can be performed to synthe- size a great variety of other compounds of the formula 1 by reactions known to the expert. If, for ex- ample, compounds of the formula 1 where R3 = -CO-NR31R32 are desired, an appropriate derivatiza- tion can be performed by methods known to the expert (e.g. conversion of an ester into a carboxylic acid and further into an amide), whereby protection of the amino functionality in 8-position with a suit- able protecting group, for example in form of a bis-fert-butyloxycarbonyl-amino group, may be required during the derivatization reactions.
Altematively, for example compounds of the formula (1) where R3 = -CO-NR31R32 can be prepared according to schema 3 by derivatization of the substituent R3 on the stage of compounds of the for- mula 5. If compounds of the formula 1 with, for example, R3 = 1-4C-alkoxycarbonyl are obtained, fur- ther chemical transformations, which are known per se, can be performed to synthesize a great variety of other compounds of the formula 1 by reactions known to the expert.
Scheme 3
R2 R2
R R3 Amide ~ ZN Cou
A LIOH A . ping
Na SPY)
LT
Arom Arom
R3 = 1-4C-alkoxycarbonyl R3 = carboxyl
R2
R3 Themal R3 = ent 2
A Rearrangem A ’
XN XN
N NH.
L oe N Mo
Arom Arom
R3 = -CO-NR31N32
The compounds of the formula 2 have at least one center of chirality in the skeleton. The invention "thus provides all feasible enantiomers of compounds of the formula 2 in any mixing ratio, including the pure enantiomers, which are a preferred subject matter of the invention.
The compounds of the formula 2a, which are a preferred subject matter of the invention,
R3 ~~ ™N \
R1 — xX N
NH (2a)
Arom can be Isolated from the corresponding racemic mixtures of the formula 2 by separating the com- pounds of the formula 2a from thelr optical antipodes by techniques known to the expert. The separa- tion can be achieved for example by crystallization of diastereomeric salts after reaction of the racemic mixture of acid free compounds of the formula 2 with a suitable, optically pure acid or by preparative chromatography using a chiral column, as described in an exemplary manner in the examples, or by other methods known to the expert.
Among the compounds of the formula 2a, those compounds are preferred wherein R1, R2, R3 and
Arom have the meanings as described above for the compounds of the formula 1.
Claims (11)
1. A compound of the formuta 1 R2 Ra A R1 = N Mow Arom where R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1 -4C-alkyl, 1- 4C-alkoxycarbonyl, 2-4C-alkenyl, fluoro-1 -4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cydoalkyl, 3.7C-cycloalkyt-1-4C-atkyi, 1-4C-alkoxycarbanyl, hy- droxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or cyanomethyl, R3 is halogen, hydroxy-14C-alky, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1- 4C-alkoxycarbonyl, fluoro-1 -4C-alkoxy-1-4C-alkyl or the radical -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-akyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkvl, 3-7C-cycloalkyl or 1-4C-alkoxy-~1-4C-alkyl, or where R31 and R32 together and including the nitrogen atom to which they are attached form a pyv- _ rolidino, piperidino or morpholino radical N Arom is a R4-, R6-, R6- and R7-substituted mono- or bicyclic aromatic radical selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-kriazolyl, indolyl, benzimida- zolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyl (ben zothienyt), thiazolyl, isoxazotyl, pyridinyl, pyrimidinyt, quinolinyl and isoquinolinyl, where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-alkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1- 4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1 4C-alkylamino or sulfonyl, RS is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-akoxycarbonyl, halogen, trifluoromethyl or hy- droxyl, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyi or halogen, where aryl Is phenyl or substituted phenyl having one, two ar three identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano, and its salts.
2. A compound of the formula 1 as claimed in claim 1, In which Ri is hydrogen, 1-4C-aliyl, 3-7C-cydoalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-atkyt, 1- 4C-alkoxycarbonyl, 2-4C-alkenyl, fluoro-1 -4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hy- droxy-1-4C-alkyl, halogen, 2-4C-akkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or cyanomethyl, R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1- 4C-alkoxycarbonyl, fluoro-1 -4C-alkoxy-1-4C-alkyl or the radical -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, piperidino or morpholino radical Arom is a R4-, R5-, R6-~ and R7-substituted mono- or bicyclic aromatic radical selected from the group consisting of phenyl, naphthyl, pyrrolyi, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimida- zolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothlopheny! (ben- zothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyi, quinolinyl and isoquinofinyl, where Rd is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-alkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, arytoxy, arvi-1- 4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino or sulfonyl, RS is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxyl, RS is hydrogen, 1-4GC-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substituted phenyl having one, two or three Identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, halogen, trifiuoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano, and its salts.
3. A-compound of the formula 1 as claimed in claim 1, in which Ri is 1-4C-alkyi, R2 is 1-4C-akyl, R3 is halogen, 1-4C-alkoxycarbonyl, or the radical -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-akoxy-1-4C-alkyl and R32 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where
R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino radical Arom Is phenyl, and its salts.
4. A compound of the formula 1 as claimed in claim 1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is halogen or 1-4C-alkoxycarbonyl, Arom is phenyl, and its salts.
5. A compound of the formula 2 R2 R3 ” a nN NH ©) Arom selected from the group consisting of 2,3-Dimethyl-8-phenyt-6,7,8,9-tetrahydro-1 ,3a,8-triaza-cyclopentalalnaphthalene-5-carboxylic acid-(2- methoxy-ethyl)-amide, » 2,3-Dimethyi-8-phenyl-6,7,8,9-tetrahydro-1 ,3a,9-tnaza-cyclopentafajnaphthalene-5-carboxylic Acid Ethyl Ester, 2,3-Dimethyl-8-phenyi-6,7,8,9-tetrahydro-1 ,3a,0-triaza-cyciopentajalnaphthalene-5-carboxylic Acid Methylamide, 2,3-Dimethyl-8-phenyi-6,7,8,9-tetrahydro-1 ,3a,9-trlaza-cyclopentafalnaphthalene-5-carboxylic Acid (2- Hydroxy-ethyl)-amide, 2,3-Dimethyl-8-phenyi-6,7,8,9-tetrahydro-1 ,3a,9-triaza-cyclopenta[alnaphthalene-5-carboxylic Acid Dimethylamide 2,3-Dimethyl-8-phenyt-6,7,8 9-tetrahydro-1 ,3a,0-triaza-cyclopentafajnaphthalene-5-carboxylic Acid Amide 1-(2,3-Dimethyl-8-pheny}-6,7,8,9-tetrahydro-1,38,9-riaza-cyclopertalajnaphthalen-5-yi}-1 -morphalin- 4-yl-methanone, 1-(2,3-Dimethyl-8-pheny}-6,7,8,8-telrahydro-1,3a,8-riaza-cyclopentafajnaphthialen-5-yi)-1 -pyrrolidin-1- yl-methanone, (2,3-Dimethyl-8-pheny}-6,7,8,9-tetrahydro-1,3a,8-triaza-cyclopentalalnaphthalen--yl} methanol, 2,3-Dimethyi-8-pheny!-6,7,8,9-tetrahydro-1 ,3a,9-triaza-cyclopentafajnaphthalene-5-carboxylic Acid Cyclopropylamide,
and its salts.
6. A compound of the formula 2a R3 peas ON NH (2a) Arom in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cydoalkyl, 3-7C~cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1- 4C-alkoxycarbonyl, 2-4C-alkenyl, fluoro-1-4C-atkyl or hydroxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 3-7C-cydoalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hy- droxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-akyl or cyanomethyl, R3 is halogen, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1 -4C-alkyl, 1- 4C-alkoxycarbonyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyi and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyt, 3-7C-cycloalkyl or 1-4C-alkaxy-1-4C-alkyl, or where R31 and R32 together and including the nitrogen atom to which they are attached form a pyr- rolidino, plperidino or morpholino radical a Arom is a R4-, R5-, R6- and R7-substituted mono- or bicyclic aromatic radical selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoiyl, 1,2,3-triazolyl, indolyl, benzimida- zolyl, furanyl (fury), benzofuranyl (benzofuryl), thiophenyl (thlenyl), benzothiophenyl (ben- zothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoguinotinyt, where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, carboxyl, 1-4C- alkoxycarbonyl, carboxy-1-4C-alkyl, halogen, hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1- 4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1 -4C-alkylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy- droxyil, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, where aryl Is phenyl or substituted phenyl having one, two or three identical or different substituents from the group consisting of 1-4C-alkyl, 1-4C-alkaxy, carboxyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano, and its salts.
7. A compound of the formula 2a R2 R3 ZN A ~~ B A N NH (2a) Arom selected from the group consisting of (8S)-2,3-Dimethyi-8-phenyi-6,7,8,9-tetrahydro-1,3a,9-triaza-cyclopentafajnaphthalene-5-carboxylic acid-(2-methoxy-ethyl)-amide, (8S)-2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-1,3a,9-riaza-cyclopentafa]naphthalene-5-carboxylic Acid Ethyl Ester, {8S)-2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-1,3a,8-triaza-cyclopentafajnaphthalene-5-carboxylic Acid Methylamide, (8S)-2,3-Dimethyl-8-phenyl-8,7,8 8-tetrahydro-1,3a,9-triaza-cyclopentalajnaphthalene-5-carboxylic Acid (2-Hydroxy-ethyl)-amide, (8S)-2,3-Dimathyl-8-phenyl-6,7,8,9-tetrahydro-1,3a,9-traza-cyclopentajalnaphthatene-5-carboxylic Acid Dimethylamide (8S)-2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-1,3a,9-triaza-cyclopenta[a]naphthalene-5-carboxylic Acid Amide (8S)-1-(2,3-Dimejhyl-8-phenyi-6,7,8,9-tetrahydro-1,3a,9-triaza-cyclopentafa]naphthalen-&:y1)-1- morpholin-4-yl-methanone (8S)-1-(2,3-Dimethyl-8-phenyl-6,7,8 9-tetrahydro-1, 3a,8-triaza-cydopentaja]naphthalen-5-yl)- 1- pyrrolidin-1-yi-methanone {8S)-(2,3-Dimethyl-8-phenyl-6,7,8,9-tetrahydro-1,3a,9-friaza-cydlopentajajnaphthalen-5-yi)-methanol (8S)-2,3-Dimethyl-8-phenyi-6,7,8,9-tetrahydro-1,3a,9-triaza-cyclopentafalnaphthalene-5-carboxylic Acid Cyclopropylamide and its salts. v
8. A process for the synthesis of a compound of the formula 2, R2 R3 ZY! Ne XN NH 2) Arom in which R1, R2, R3 and Arom have the meanings as In claim 1, which comprises the conversion of a compound of the formula 1 as claimed in claim 1 into a compound of the formula 2, followed ,if de- sired, by further derivatization of the resulting compound of the formula 2 into another compound of the formula 2.
9. A process for the synthesis of a compound of the formula 1 as claimed In claim 1, which com- prises the conversion of a compound of the formula 5, in which R1, R2, R3 and Arom have the mean- ings as indicated in claim 1, into the corresponding compound of the formula 1, followed if desired, by further derivatization of the resulting compound of the formula 1 into another compound of the formula
1. R2 R2 R3 R3 ~~ A ~~ ay Rt ——— R1 =~ — A N XN N NH N L ©) x Meo Arom Arom
10. A medicament comprising a compound as claimed in claim 5, claim 6 or claim 7 and/or a phar- macologically acceptable salt thereof together with customary pharmaceutical auxitiaries and/or ex- cipients.
11. The use of a compound as claimed in claim 5, claim 6 or claim 7 and/or its pharmacologically acceptable salts for the prevention and treatment of gastrointestinal disorders.
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| WO2005051298A2 (en) | 2003-11-19 | 2005-06-09 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
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| CA2606499C (en) | 2005-05-26 | 2017-06-13 | Metabasis Therapeutics, Inc. | Thyromimetics for the treatment of fatty liver diseases |
| MX2007014501A (en) * | 2005-05-26 | 2008-02-07 | Metabasis Therapeutics Inc | Novel phosphinic acid-containing thyromimetics. |
| US8486921B2 (en) * | 2006-04-07 | 2013-07-16 | President And Fellows Of Harvard College | Synthesis of tetracyclines and analogues thereof |
| EP2479169B1 (en) | 2006-10-11 | 2014-12-03 | President and Fellows of Harvard College | Synthesis of Enone Intermediate |
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| US9073829B2 (en) | 2009-04-30 | 2015-07-07 | President And Fellows Of Harvard College | Synthesis of tetracyclines and intermediates thereto |
| CN101659676B (en) * | 2009-09-07 | 2012-06-20 | 徐奎 | Sulfo-Adefovir and Tenofovir liver targeting ester prodrug |
| CN102850402B (en) * | 2011-06-28 | 2016-08-03 | 李勤耕 | Acyclonucleosides cyclic phosphate esters derivative, its preparation method and medical usage |
| JP6508944B2 (en) | 2012-02-15 | 2019-05-08 | サイデックス・ファーマシューティカルズ・インコーポレイテッド | Method of preparation for cyclodextrin derivatives |
| CA2865950C (en) | 2012-02-28 | 2016-12-20 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
| CN107312039B (en) | 2012-08-30 | 2019-06-25 | 江苏豪森药业集团有限公司 | A kind of preparation method of tenofovir prodrug |
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- 2005-06-03 RU RU2006138907/04A patent/RU2006138907A/en not_active Application Discontinuation
- 2005-06-03 WO PCT/US2005/019440 patent/WO2005123729A1/en active Application Filing
- 2005-06-03 KR KR1020067026296A patent/KR20070029196A/en not_active Application Discontinuation
- 2005-06-03 CN CN201310268311.1A patent/CN103374041B/en active Active
- 2005-06-03 CN CN200580018611.8A patent/CN1964967B/en active Active
- 2005-06-03 AU AU2005254940A patent/AU2005254940A1/en not_active Abandoned
- 2005-06-03 JP JP2007527592A patent/JP5142716B2/en active Active
- 2005-06-03 US US11/144,348 patent/US7582758B2/en active Active
- 2005-06-03 EP EP05758526.7A patent/EP1753762B1/en active Active
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- 2005-06-03 BR BRPI0511948-0A patent/BRPI0511948A/en not_active IP Right Cessation
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- 2005-06-08 TW TW094118835A patent/TWI370819B/en not_active IP Right Cessation
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2006
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| CN1964967B (en) | 2014-04-16 |
| CN103374041A (en) | 2013-10-30 |
| TWI370819B (en) | 2012-08-21 |
| MXPA06014013A (en) | 2007-03-15 |
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| AU2005254940A1 (en) | 2005-12-29 |
| RU2006138907A (en) | 2008-07-20 |
| JP2008501799A (en) | 2008-01-24 |
| CA2565966A1 (en) | 2005-12-29 |
| EP1753762A4 (en) | 2011-05-04 |
| WO2005123729A1 (en) | 2005-12-29 |
| EP1753762A1 (en) | 2007-02-21 |
| US20050282782A1 (en) | 2005-12-22 |
| CN1964967A (en) | 2007-05-16 |
| BRPI0511948A (en) | 2008-01-29 |
| CN103374041B (en) | 2017-05-10 |
| US7582758B2 (en) | 2009-09-01 |
| TW200617008A (en) | 2006-06-01 |
| EP1753762B1 (en) | 2014-03-19 |
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